Malaria remains a devastating global health problem, resulting in up to one million annual deaths (see, e.g., Sachs, Science (2002) 298:122-124; Mwangi et al., J Infect Dis (2005) 191:1932-1939; Snow et al., Nature (2005) 434:214-217; World Health Organization (WHO). World malaria report 2008). Plasmodium falciparum causes the most severe forms of malaria infection such as cerebral malaria (CM) and acute lung injury (ALI) (see, e.g., Trampuz et al., Crit Care (2003) 7:315-323). The case-fatality rate in severe malaria treated with either artemisinin or quinine derivatives remains unacceptably high. Cerebral malaria is among the deadliest syndromes with 13-21% mortality even after anti-malarial treatment (see, e.g., Idro et al., Lancet Neurol (2005) 4:827-840).
Primary therapy with quinine or artemisinin derivatives is generally effective in controlling P. falciparum parasitemia, but mortality from cerebral malaria (CM) and other forms of severe malaria remains unacceptably high. In an effort to reduce malaria-related mortality adjunctive/adjuvant therapies complementing treatment to an anti-malarial therapy have been suggested and tested (see, e.g., John et al., Expert Rev Anti Infect Ther (2010) 8:997-1008). Heme oxygenase-1 (HO-1) is a key protective gene against the development of CM in mice (see, e.g., Pamplona et al., Nat Med (2007) 13:703-710). Inhalation of carbon monoxide (CO), one of the end-products of HO-1 activity, fully prevented cerebral malaria and malaria-associated acute lung injury (M-AALI) incidence in C57BL/6 mice (see, e.g., Pamplona supra; Epiphanio et al., PLoS Pathog (2010) 6:e1000916). Research conducted in other experimental models has further shown that HO-1/CO display cytoprotective and anti-inflammatory properties that are beneficial for the resolution of acute inflammation (see, e.g., Hayashi et al., Circ Res (1999) 85:663-671; Lee et al., Nat Med (2002) 8:240-246).
Carbon monoxide holds great promise as a therapeutic agent (see, e.g., Motterlini et al., Nat Rev Drug Discov (2010) 9:728-743). However, the safety and practicability of the application of carbon monoxide gas in the clinic remains questionable due to its toxicity and the need for highly controlled medical facilities. Thus, CO-releasing molecules (CO-RMs) have been put forward as a valid alternative. Among the early-developed and still widely used CO-RMs in experimental models are the lipid-soluble CORM-2, [Ru(CO)3Cl2]2, and the water-soluble CORM-3, [Ru(CO)3Cl2(H2NCH2CO)2]. Both CORM-2 and CORM-3 do not elevate the carboxyhemoglobin (COHb) levels in blood after in vivo administration (see, e.g., Clark et al., Circ Res (2003) 93:2-8). Substantial protective effects similar to those observed for CO inhalation have been reported using CORM-2 and CORM-3 in various experimental models of disease, such as bacterial infection, vascular dysfunction, and thermal- and ischemia-reperfusion injury (see, e.g., Clark supra; Alcaraz et al., Curr Pharm Des (2008) 14:465-72); Kim et al., Annu Rev Pharmacol Toxicol (2006) 46:411-449). Moreover, CORM-2 lacks desirable drug-like properties, such as water solubility and stability in its own solvent (see Motterlini et al., Circ Res (2002) 90:e17-e24). Thus, there continues to remain a need for the development of new CORMs as therapeutic agents.